Tumor growth is dependent on a kinetic model that is based on the progression of cell proliferation and cell loss. The parameters for cell proliferation during tumor progression include the cell cycle time (Tc), growth fraction (GF), and potential tumor doubling time (Tpot). In contrast, the cell-loss factor is determined by Tpot and the actual time for doubling of the tumor volume (Td) (Steel G G., 1967, Eur J Cancer 3(4):381-387). The causes of cell loss include malnutrition and lack of oxygen caused by rapid proliferation, necrosis and apoptosis, immunological attack, escape from the primary site, and exfoliation (Cooper E H, et al., 1975, Advances in cancer research 21:59-120). These conditions can be regarded as stresses for cells residing in a rapidly growing tumor. Whether cells escaping from these stresses inherit or obtain resistance abilities is unknown.
The tracking and characterization of live cells in a tumor are important for cancer treatment. Reporter gene imaging is an indirect approach to labeling cells for imaging-based in vivo tracking and targeting by different modalities (Serganova I, et al., 2008, Handb Exp Pharmacol (185 Pt 2): 167-223). This method is especially important for tracking cell viability in vivo because gene transcription and translation occur only in live cells (Acton P D, Zhou R., 2005, J Nucl Med Mol Imaging 49(4): 349-360). In addition, the transmission of genes to progeny is in principle not diminished or diluted if the reporter genes can replicate within the genomes of host cells (Kircher M F, et al., 2011, Nat Rev Clin Oncol 8(11): 677-688). Firefly luciferase and fluorescent proteins are canonical reporter genes used for bioluminescent imaging and optical imaging, respectively. For radionuclide-based reporter gene imaging, herpes simplex virus type 1-thymidine kinase (HSV1-tk) is commonly used because it can uptake a broad range of radiolabeled nucleoside analogues for imaging the target cells in vivo (Diehn M, Clarke M F, 2006, J Natl Cancer Inst 98(24):1755-1757). Expression of the HSV1-tk reporter gene can be used for live cell tracking by positron emission tomography (PET) or single photon emission computed tomography (SPECT), depending on the types of radionuclide-labeled substrates. Multimodality reporter gene imaging using co-expressed luciferase/fluorescent proteins and HSV1-tk has been reported to be a powerful tool for basic biological and preclinical research (Love Z, Wang F, Dennis J, et al., 2007, J Nucl Med 48(12):2011-2020; Ray P., 2011, Curr Pharm Biotechnol 12(4):539-546). In addition, PET and SPECT can be merged with computed tomography (CT) to obtain functional/anatomic imaging with high sensitivity and spatial resolution.
Cancer stem cells (CSCs, or cancer initiating cells) belong to the hierarchy model that a subset of rare cell population inherits stem cell-like characteristics, including self-renewal and generation of non-tumorigenic progeny (Reya T, et al., 2001, Nature 414(6859):105-111). This theory has intrigued many researchers in recent years because CSCs are resistant to chemo-radiotherapy and are likely to be the cause of tumor recurrence and metastasis (Zhang M, Rosen J M. 2006, Curr Opin Genet Dev 16(1):60-64). However, the identification of CSCs in vivo remains a challenge because of the lack of suitable markers for this purpose. If CSCs naturally resist environmental stresses, it would be speculated that this population may also escape from cell loss during tumor progression. More evidence is required to support this hypothesis.